image: COVID-19 patient whole blood sequencing data was analyzed for chimeric RNA using STARfusion, SoapFuse, and EricScript. Predictions found by at least two software and those containing no middle-to-middle (M:M) chimeric splice junctions were kept. All high-confidence predictions were used for downstream analysis. Downstream analysis included expression profiling, pathway enrichment, motif enrichment, and chi-square contingency tables. High confidence predictions were also further filtered to remove chimeras found in GTEx samples and spurious results found in less than five patients. Finally, PCR and Sanger sequencing were used to validate recurrent, COVID-19-specific chimeras, and the chimeras found to have an association with age, sex, or disease status.
Credit: Genes & Diseases
The COVID-19 pandemic has had a detrimental impact on global health. The momentous effort of researchers around the globe resulted in not only the successful development of multiple vaccines but also a vast accumulation of COVID-19 patient-derived next-generation sequencing data. Despite the availability of efficacious vaccines, COVID-19 persists, and our knowledge of host transcriptomics is still vague.
In a recent study published in the Genes & Diseases journal, researchers from the University of Virginia, Huazhong University of Science and Technology, CSIR-Indian Institute of Toxicology Research, and Zhengzhou University demonstrated the potential of chimeric RNAs as biomarkers of COVID-19 infection. For this purpose, the authors assessed and characterized chimeric RNAs from whole blood samples of 178 COVID-19 patients.
The authors used three different chimeric RNA prediction software tools—STAR-Fusion, SOAPfuse, and EricScript—to identify chimeric RNA transcripts in whole blood samples from COVID-19 patients. This resulted in over 30,000 predictions, with approximately 500 high-confidence predictions representing 328 unique parental gene pairs “that were found by more than one software and filtered based on exon annotations around the chimeric splice junction".
Using uniform manifold approximation and projection (UMAP) and simple matching coefficients (SMC), the authors observed that i) the expression of chimeric RNAs in whole blood differs between symptomatic and asymptomatic COVID-19 patients and ii) the binary expression profiles of chimeric and parental transcripts are also different, suggesting that the chimeric RNAs have an additional layer of transcriptional control.
GLAM2 and Tomtom identified several RNA-binding proteins (RBPs) with enriched motifs in the upstream and downstream regions flanking, both the 5′ and 3′ junction sites. The RNA-binding protein motifs of SFPQ and PTBP1 were found to be the top enriched RBP motifs in COVID-19 patient chimeras. Previous studies have implicated PTBP1 in other coronavirus infections as associated with increased virus production.
Subsequent analysis identified that the ODF3B (ciliary microtubule-associated protein 1B)–SCO2 (synthesis of cytochrome c oxidase 2) (OS) and TYMP (thymidine phosphorylase)-SCO2 (TS) chimeric isoforms comprised the majority of the 14 chimeras found only in the PTBP1 knockdown and COVID-19 samples. The OS and TS transcript displayed a strong correlation with disease status. PTBP1 also appeared to be involved in IFN signaling, which correlates with the COVID-19 asymptomatic patient data.
In conclusion, the authors identified over 300 chimeric RNA transcripts in COVID-19 patient whole blood samples that were not found in the GTEx whole blood samples. The findings of this study demonstrate that “PTBP1 interacting mRNA transcripts, such as chimeric OS and TS, may serve as valuable biomarkers for the early-stage presence of viral infection even when symptoms of infection are not observed and viral RNA is undetectable in the blood”.
Reference
Title of the original paper: Landscape of chimeric RNAs in COVID-19 patient blood
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101348
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